The research program of CRGGH is conducting multiple studies in the genomics of cardiometabolic disorders and other complex traits. Type 2 diabetes (T2D) has been a primary focus of the lab as exemplified by the lab's leading of the Africa America Diabetes Mellitus (AADM) study, the longest running genetic epidemiology study of T2D in Africa. AADM has now enrolled over 6,000 cases of T2D and controls, and the analytic techniques applied have ranged through linkage analysis, candidate gene association studies, genome-wide association approaches and whole exam sequencing. The AADM study has been extremely successful with several publications in high impact journals. For example, the AADM study, in collaboration with deCODE Genetics, made significant contribution in 2007 to the global understanding of the genetic basis of diabetes by identifying a gene (TCF7L2) for T2D that subsequently became the most consistently replicated. CRGGH has completed the genotyping of 2,000 Africans with diabetes and controls to conduct the first GWAS in Africans for T2D. A manuscript describing transferability and fine mapping of established T2D loci is currently under review. Analysis of this unique data is ongoing. CRGGH has also identified multiplex families with T2D, reasoning that these families are enriched for variants with larger effect sizes and higher penetrance than those loci commonly associated with complex diseases. Whole-exome sequencing has been completed by NISC on a set of such families, including African American families and West African families. Data analysis is ongoing. CRGGH investigators are co-applicant of the newly funded project entitled Burden, Spectrum and Etiology of T2D in sub Saharan Africa. This five-year 3M Wellcome Trust H3Africa award is funding a consortium of 16 centers in 9 African countries, the UK, and the US to enroll 12,000 T2D cases and 12,000 controls. CRGGH has also contributed to several international T2D consortia, including the Meta-analysis of T2D in Africa Americans (MEDIA) Consortium, in an analysis of 17 GWAS for T2D in over 8,000 cases and 16,000 controls was performed. Genetics of dyslipidemia: In contrast to the increased prevalence of hypertension, T2D, and obesity observed with increasing degree of westernization, there is remarkable similarity in the distribution of serum lipid parameters across populations of the African Diaspora. In the US, interethnic differences in serum lipid distributions are consistently observed, with African Americans having a generally healthier lipid profile, characterized by lower TG and higher HDL, than European Americans. These results are found despite differences in lifestyle factors that would be expected to produce a worse lipid profile among AA. To shed light on these observations, we evaluated 5 lipid candidate genes to identify variants with ethnicity-specific effects. We sequenced ABCA1, LCAT, LPL, PON1, and SERPINE1 in 48 AA individuals with extreme serum lipid concentrations. Identified variants were genotyped in 1694 and tested for an association with serum lipids. We demonstrated significant ethnic specific effects on HDL and TG (Bentley et al PLoS Genetics 2014). We are currently conducting more comprehensive studies of the genomic epidemiology of dyslipidemia using sequencing approaches. We also continue to participate in consortia investigating the genetics of various aspects of obesity, adiposity measures and insulin biology as exemplified by two recent publications (Shungin et al Nature 2015; Locke et al Nature 2015). Recognizing the interrelated nature and clustering of metabolic disorders such hypertension, obesity, insulin resistance, T2D, dyslipidemia and kidney function, we are currently conducting studies designed to uncover pleiotropic loci using an exome array approach. These studies should identify those genetic loci that influence risk to multiple traits and, hopefully, provide insight into the underlying biological mechanisms that lead to such co-occurrence of cardiometabolic traits. Genetic Epidemiology of Podoconiosis: Podoconiosis (Podo) remains a major focus of CRGGH. The disease is a devastating, stigmatizing, and neglected tropical disease characterized by lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. It is entirely preventable by wearing shoes. Not all exposed persons develop the disease, and we have shown that Podo is highly heritable (h2 63%). So far, research projects conducted by our team have shed light on the clinical staging of Podo; the economic, ethical, and social issues surrounding the implementation of genomic research in resource-poor settings; the use of genetic information to improve primary prevention strategies; and the genetic basis of Podo (NEJM 2011). Working with collaborators in the UK, Germany, Ethiopia and Cameroon, we are currently extending these studies using a combination of new field studies in Cameroon and Ethiopia, GWAS array genotyping, transcriptomics studies and whole exam sequencing. The resulting data will form the most comprehensive genomic dataset available on podoconiosis. Studies of Benign Ethnic Neutropenia (BEN) are ongoing in collaboration with Dr. Griffin Rodgerss (NIDDK) lab and Dr. Bill Flegel (CC). The initial studies involved genome-wide association analysis and admixture mapping in a sample of 1200 African Americans. Subsequently, we have conducted gene expression and pathway analyses. Currently, we are conducting functional studies of prioritized loci. Statistical Approaches and Methods Development: CRGGH investigators are internationally recognized expertise in the analysis of complex traits in admixed African Americans and other African Diaspora populations, as exemplified by a recent invited review on mapping disease-associated variants in admixed populations published in Genome Biology and an American Society of Human Genetics 2010 invited session Complex Disease Genetics Research in Admixed Populations. We have also developed tools that respond to the changing resources and challenges of the field as a whole: novel approaches for the simultaneous analysis of common and rare variants, approximate and exact tests of Hardy-Weinberg equilibrium using uncertain genotypes, and a test for gene-gene interactions in case-control studies. Our most recent contributions include an improved Fst test and methods for estimating population-specific multiple testing burden in genome wide association studies. CRGGHs work in population genomics retains high priority. Recent projects include: African Genome Variation Project (AGVP): In collaboration with investigators at the Sanger Institute (UK) and institutions across Africa, we established the AGVP in which we used the Illumina 2.5M chip to genotype 100 individuals from each of 18 ethnic groups from Africa. CRGGH investigators are analyzing generated data with the promise of informing genomic studies in Africa by providing a reference for allelic, haplotype, and LD structure for common variants in populations not covered by HapMap and the 1000 Genomes projects. Understanding Human History: Using genome-wide genotype data from 3,528 individuals sampled from 163 human ethno-linguistic groups around the world, we identified 19 global ancestral components that tracked geography or linguistic groupings, both well-known barriers to gene flow. We observed that 94.4% of individuals had mixed ancestry, with profound implications for understanding human evolutionary history and health. More recently, we have done genome-wide studies of adaptation in African populations, including a genome-wide analysis for evidence of recent positive selection. The genetic, ecological, and socio-cultural diversities of Africans promise to contribute to the global understanding of human adaptation.